tbuckley/cabot-search huggingface dataset:
Thrombosis in multiple myeloma: Risk estimation by induction regimen and association with overall survival
Authors: Charalampos Charalampous, Utkarsh Goel, Prashant Kapoor, Moritz Binder, Francis K. Buadi, David Dingli, Angela Dispenzieri, Amie L. Fonder, Morie A. Gertz, Wilson Gonsalves, Suzanne R. Hayman, Miriam A. Hobbs, Yi L. Hwa, Taxiarchis Kourelis, Martha Q. Lacy, Nelson Leung, Yi Lin, Rahma Warsame, Robert A. Kyle, S. Vincent Rajkumar, Shaji Kumar
Journal: American Journal of Hematology (2023)

Abstract Lenalidomide‐containing (R) triplet and quadruplet regimens are the standard of care for multiple myeloma (MM) and have been shown to increase the risk of thrombosis. The association between thromboembolism (TE) and survival in the novel multidrug era is not yet delineated. In this study, we evaluated the incidence of TE during the first year of MM diagnosis, its association with the type of induction regimen, and its impact on overall survival. We studied 672 newly diagnosed MM (NDMM) patients who received a triplet or quadruplet lenalidomide‐based induction at the Mayo Clinic, Rochester. TE was diagnosed in 83 patients (12.4%). Of these, 56 (8.3%) had a deep venous thrombosis (DVT), 23 (3.4%) had a pulmonary embolism (PE) with or without the DVT, and 4 (0.6%) patients had a stroke. Carfilzomib‐Rd (KRd) had the highest risk of TE (21.1%, 18/85), followed by quadruplets (11.1%, 5/45), bortezomib‐Rd (9.6%, 51/531), and 0/11 (0%), treated with other lenalidomide‐containing regimens. The difference in TE risk between KRd and the other regimens was statistically significant (OR = 2.6, p &lt; .01). Nine patients developed a TE before being exposed to any treatment. Survival was significantly lower among patients that developed a TE (66 vs. 133 months, p &lt; .01). The association of TE with reduced survival demonstrated in univariate analysis (HR = 2.2, 95% CI = 1.6–3.3) was maintained in the multivariable analysis adjusted for high‐risk interphase fluorescence in situ hybridization (FISH), sex, age, receipt of an upfront transplant, the response at induction, and the International Staging System (ISS) (HR = 2.61, CI = 1.74–3.9). We conclude that TE is an important aspect of MM management, and effective management is especially relevant in the novel treatment era.
Waldenström macroglobulinemia: 2023 update on diagnosis, risk stratification, and management
Authors: Morie A. Gertz
Journal: American Journal of Hematology (2023)

Abstract Disease Overview Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. Diagnosis Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in most IgM MGUS patients. MYD88 is not required for the diagnosis. Risk Stratification Age, hemoglobin level, platelet count, β 2 microglobulin, LDH, and monoclonal IgM concentrations are characteristics that are predictive of outcomes. Risk‐Adapted Therapy Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab‐monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or a BTK inhibitor. The preferred Mayo Clinic induction is either rituximab and bendamustine (without rituximab maintenance) or zanubrutinib. Management of Refractory Disease Bortezomib, cyclophosphamide, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, bendamustine, and venetoclax have all been shown to have activity in relapsed WM. Given WM's natural history, the reduction of therapy toxicity is an important part of treatment selection.
miRNome profiling of lung cancer metastases revealed a key role for miRNA-PD-L1 axis in the modulation of chemotherapy response
Authors: Roberto Cuttano, Tommaso Colangelo, Juliana Guarize, Elisa Dama, Maria Pia Cocomazzi, Francesco Mazzarelli, Valentina Melocchi, Orazio Palumbo, Elena Marino, Elena Belloni, Francesca Montani, Manuela Vecchi, Massimo Barberis, Paolo Graziano, Andrea Pasquier, Julian Sanz-Ortega, Luis M. Montuenga, Cristiano Carbonelli, Lorenzo Spaggiari, Fabrizio Bianchi
Journal: Journal of Hematology & Oncology (2022)

Abstract Locally advanced non-small cell lung cancer (NSCLC) is frequent at diagnosis and requires multimodal treatment approaches. Neoadjuvant chemotherapy (NACT) followed by surgery is the treatment of choice for operable locally advanced NSCLC (Stage IIIA). However, the majority of patients are NACT-resistant and show persistent lymph nodal metastases (LNmets) and an adverse outcome. Therefore, the identification of mechanisms and biomarkers of NACT resistance is paramount for ameliorating the prognosis of patients with Stage IIIA NSCLC. Here, we investigated the miRNome and transcriptome of chemo-naïve LNmets collected from patients with Stage IIIA NSCLC ( N = 64). We found that a microRNA signature accurately predicts NACT response. Mechanistically, we discovered a miR-455-5p/PD-L1 regulatory axis which drives chemotherapy resistance, hallmarks metastases with active IFN-γ response pathway (an inducer of PD-L1 expression), and impacts T cells viability and relative abundances in tumor microenvironment (TME). Our data provide new biomarkers to predict NACT response and add molecular insights relevant for improving the management of patients with locally advanced NSCLC.
Retraction Notice to: Insulin-like Growth Factor-binding Protein-7 (IGFBP7): A Promising Gene Therapeutic for Hepatocellular Carcinoma (HCC)
Authors: Dong Chen, Ayesha Siddiq, Luni Emdad, Devaraja Rajasekaran, Rachel Gredler, Xue-Ning Shen, Prasanna K. Santhekadur, Jyoti Srivastava, Chadia L. Robertson, Igor Dmitriev, Elena A. Kashentseva, David T. Curiel, Paul B. Fisher, Devanand Sarkar
Journal: Molecular Therapy (2022)
Locomotor Brachii Sign in Aortic Regurgitation
Authors: Gonzalo Barge-Caballero, Cayetana Barbeito-Caamaño
Journal: New England Journal of Medicine (2022)

A 60-year-old man presented with a 3-month history of dyspnea on exertion. His blood pressure was 141/55 mm Hg. There was a grade 3/4 diastolic murmur and tortuous, visibly pulsatile brachial arteries (shown in a video).
Resisting T cell attack: tumor-cell-intrinsic defense and reparation mechanisms
Authors: Brienne McKenzie, Salvatore Valitutti
Journal: Trends in cancer (2022)

Cytotoxic T lymphocytes (CTLs) are antigen-specific killer cells equipped to identify and eliminate host cells that have been altered through infection or transformation. Both chimeric antigen-receptor (CAR) T cell therapies and immune checkpoint blockade (ICB) therapies are based on successful elimination of tumor cells by cytotoxic effectors. In this opinion article, we outline cell-intrinsic mechanisms by which tumor cells defend against CTLs, highlighting pathways that confer resistance and proposing opportunities for combination therapies. We discuss how exogenous killing entities [e.g., supramolecular attack particles (SMAPs)] offer a novel strategy to circumvent cellular resistance mechanisms. Our opinion article highlights the importance of identifying, quantifying, and targeting tumor defense mechanisms at the interface between tumor cells and CTLs as a critical consideration in the development of immunotherapy approaches.
Digital media use and sleep in late adolescence and young adulthood: A systematic review
Authors: Louise AS. Brautsch, Lisbeth Lund, Martin M. Andersen, Poul J. Jennum, Anna P. Folker, Susan Andersen
Journal: Sleep Medicine Reviews (2022)

Despite much attention on digital media use and young peoples' sleep, the literature on digital media and its impact on sleep in older adolescents and young adults remains to be synthesized. We conducted a systematic review of studies including young people aged 16-25 years. We searched Medline, Web of Science, and CINAHL for observational studies, identifying 60 studies. These studies were assessed for methodological quality. Only studies rated as moderate or high-quality studies were included (n = 42). A narrative synthesis summarized the impact of digital media use on eight sleep outcomes: Bedtime; Sleep onset latency or problems falling asleep; Sleep duration; Early awakening; Sleep disturbance; Daytime tiredness and function; Sleep deficits; Sleep quality. In summary, digital media use was associated to shorter sleep duration and poorer sleep quality. These associations were found for general screen use and use of mobile phone, computer, internet, and social media, but not for television, game console, and tablet use. Most studies investigating bedtime or nighttime use found associations to poor sleep outcomes. Later bedtime and daytime tiredness were associated with mobile phone use at night. Additional research is warranted to draw solid conclusions about the causal direction and to understand the underlying mechanisms.
Anatomical determinants of upper airway collapsibility in obstructive sleep apnea: A systematic review and meta-analysis
Authors: Phillip J. Hartfield, Jaroslaw Janczy, Abhay Sharma, Hillary A. Newsome, Rodney A. Sparapani, John S. Rhee, B. Tucker Woodson, Guilherme J.M. Garcia
Journal: Sleep Medicine Reviews (2022)
Comparative efficacy of tezepelumab to mepolizumab, benralizumab, and dupilumab in eosinophilic asthma: A Bayesian network meta-analysis
Authors: Tanawin Nopsopon, Grace Lassiter, Ming-Li Chen, G. Caleb Alexander, Corinne Keet, Hwanhee Hong, Ayobami Akenroye
Journal: Journal of Allergy and Clinical Immunology (2022)
The impact of social isolation from COVID-19-related public health measures on cognitive function and mental health among older adults: A systematic review and meta-analysis
Authors: Prapichaya Prommas, Kaung Suu Lwin, Yi Chi Chen, Misa Hyakutake, Cyrus Ghaznavi, Haruka Sakamoto, Hiroaki Miyata, Shuhei Nomura
Journal: Ageing Research Reviews (2022)

We aimed to estimate the impact of social isolation on cognitive function and mental health among older adults during the two-year-and-a-half COVID-19 period. Pubmed Central, Medline, CINAHL Plus and PsychINFO were searched between March 1, 2020, and September 30, 2022. We included all studies that assessed proportions of older adults with the mean or the median with a minimum age above 60 reporting worsening cognitive function and mental health. Thirty-two studies from 18 countries met the eligibility criteria for meta-analyses. We found that the proportions of older adults with dementia who experienced worsening cognitive impairment and exacerbation or new onset of behavioral and psychological symptoms of dementia (BPSD) were approximately twice larger than that of older adults with HC experiencing SCD and worsening mental health. Stage of dementia, care options, and severity of mobility restriction measures did not yield significant differences in the number of older adults with dementia reporting worsening cognitive impairment and BPSD, while the length of isolation did for BPSD but not cognitive impairment. Our study highlights the impact of social isolation on cognitive function and mental health among older adults. Public health strategies should prioritize efforts to promote healthy lifestyles and proactive assessments.
Newly developed gas-assisted sonodynamic therapy in cancer treatment
Authors: Meng Pan, Danrong Hu, Liping Yuan, Yan Yu, Yicong Li, Zhiyong Qian
Journal: Acta Pharmaceutica Sinica B (2022)

Sonodynamic therapy (SDT) is an emerging noninvasive treatment modality that utilizes low-frequency and low-intensity ultrasound (US) to trigger sensitizers to kill tumor cells with reactive oxygen species (ROS). Although SDT has attracted much attention for its properties including high tumor specificity and deep tissue penetration, its anticancer efficacy is still far from satisfactory. As a result, new strategies such as gas-assisted therapy have been proposed to further promote the effectiveness of SDT. In this review, the mechanisms of SDT and gas-assisted SDT are first summarized. Then, the applications of gas-assisted SDT for cancer therapy are introduced and categorized by gas types. Next, therapeutic systems for SDT that can realize real-time imaging are further presented. Finally, the challenges and perspectives of gas-assisted SDT for future clinical applications are discussed.
A Cell‐Free Silk Fibroin Biomaterial Strategy Promotes In Situ Cartilage Regeneration Via Programmed Releases of Bioactive Molecules (Adv. Healthcare Mater. 1/2023)
Authors: Zhinan Mao, Xuewei Bi, Chengai Wu, Yufeng Zheng, Xiong Shu, Sujun Wu, Juan Guan, Robert O. Ritchie
Journal: Advanced Healthcare Materials (2023)
Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy
Authors: Jie Dai, Xue Bai, Xuan Gao, Lirui Tang, Yu Chen, Linzi Sun, Xiaoting Wei, Caili Li, Zhonghui Qi, Yan Kong, Chuanliang Cui, Zhihong Chi, Xinan Sheng, Zelong Xu, Bin Lian, Siming Li, Xieqiao Yan, Bixia Tang, Li Zhou, Xuan Wang, Xuefeng Xia, Jun Guo, Lili Mao, Lu Si
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Accumulating data suggest that mucosal melanoma, well known for its poor response to immune checkpoint blockade (ICB) and abysmal prognosis, is a heterogeneous subtype of melanoma with distinct genomic and clinical characteristics between different anatomic locations of the primary lesions. Primary malignant melanoma of the esophagus (PMME) is a rare, highly aggressive disease with a poorer prognosis compared with that of non-esophageal mucosal melanoma (NEMM). In this study, we retrospectively analyzed the efficacy of anti-programmed death (PD)-1 in patients with PMME and explored its molecular basis. Methods The response and survival of patients with PMME and NEMM under anti-PD-1 monotherapy were retrospectively analyzed. To explore the molecular mechanisms of the difference in therapeutic efficacy between PMME and NEMM, we performed genomic analysis, bulk RNA sequencing, and multiplex immunohistochemistry staining. Results We found that PMME (n=28) responded better to anti-PD-1 treatment than NEMM (n=64), with a significantly higher objective response rate (33.3% (95% CI 14.3% to 52.3%) vs 6.6% (95% CI 0.2% to 12.9%)) and disease control rate (74.1% (95% CI 56.4% to 91.7%) vs 37.7% (95% CI 25.2% to 50.2%)). Genomic sequencing analysis revealed that the genomic aberration landscape of PMME predominated in classical cancer driver genes, with approximately half of PMME cases harboring mutations in BRAF , N/KRAS , and NF1 . In contrast, most NEMM cases were triple wild-type. Transcriptome analysis revealed that, compared with NEMM, PMME displayed more significant proliferation and inflammatory features with higher expression of genes related to antigen presentation and differentiation, and a less immunosuppressive signature with lower expression of inhibitory immune checkpoints and dedifferentiation-related genes. The multiplex immunohistochemical analysis also demonstrated higher CD8 + T-cell infiltration in PMME than in NEMM. Conclusions PMME is an outlier of mucosal melanoma showing a malicious phenotype but a particularly high response rate to ICB because of its distinct molecular characteristics. Patient stratification based on anatomic origin can facilitate clinical decision-making in patients with mucosal melanoma following the verification of our results in future prospective studies.
CD4 CAR-T cells targeting CD19 play a key role in exacerbating cytokine release syndrome, while maintaining long-term responses
Authors: Camilla Bove, Silvia Arcangeli, Laura Falcone, Barbara Camisa, Rita El Khoury, Beatrice Greco, Anna De Lucia, Alice Bergamini, Attilio Bondanza, Fabio Ciceri, Chiara Bonini, Monica Casucci
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background To date, T cells redirected with CD19-specific chimeric antigen receptors (CAR) have gained impressive success in B-cell malignancies. However, treatment failures are common and the occurrence of severe toxicities, such as cytokine release syndrome (CRS), still limits the full exploitation of this approach. Therefore, the development of cell products with improved therapeutic indexes is highly demanded. Methods In this project, we investigated how CD4 and CD8 populations cooperate during CD19 CAR-T cell responses and what is their specific role in CRS development. To this aim, we took advantage of immunodeficient mice reconstituted with a human immune system (HuSGM3) and engrafted with the B-cell acute lymphoblastic leukemia cell line NALM-6, a model that allows to thoroughly study efficacy and toxicity profiles of CD19 CAR-T cell products. Results CD4 CAR-T cells showed superior proliferation and activation potential, which translated into stronger stimulation of myeloid cells, the main triggers of adverse events. Accordingly, toxicity assessment in HuSGM3 mice identified CD4 CAR-T cells as key contributors to CRS development, revealing a safer profile when they harbor CARs embedded with 4-1BB, rather than CD28. By comparing differentially co-stimulated CD4:CD8 1:1 CAR-T cell formulations, we observed that CD4 cells shape the overall expansion kinetics of the infused product and are crucial for maintaining long-term responses. Interestingly, the combination of CD4.BBz with CD8.28z CAR-T cells resulted in the lowest toxicity, without impacting antitumor efficacy. Conclusions Taken together, these data point out that the rational design of improved adoptive T-cell therapies should consider the biological features of CD4 CAR-T cells, which emerged as crucial for maintaining long-term responses but also endowed by a higher toxic potential.
Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity
Authors: Marc Pfefferlé, Irina L Dubach, Raphael M Buzzi, Elena Dürst, Nadja Schulthess-Lutz, Livio Baselgia, Kerstin Hansen, Larissa Imhof, Sandra Koernig, Didier Le Roy, Thierry Roger, Rok Humar, Dominik J Schaer, Florence Vallelian
Journal: Journal for ImmunoTherapy of Cancer (2023)

Agonistic anti-CD40 monoclonal antibodies (mAbs) have emerged as promising immunotherapeutic compounds with impressive antitumor effects in mouse models. However, preclinical and clinical studies faced dose-limiting toxicities mediated by necroinflammatory liver disease. An effective prophylactic treatment for liver immune-related adverse events that does not suppress specific antitumor immunity remains to be found.
Modulation of myeloid and T cells in vivo by Bruton’s tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma
Authors: Meenal Sinha, Courtney Betts, Li Zhang, Madeline J Griffith, Isabelle Solman, Brandon Chen, Eric Liu, Whitney Tamaki, Jacob Stultz, Jaqueline Marquez, Shamilene Sivagnanam, Alexander Cheung, Denise Pener, Anne Fahlman, Erin Taber, Kimberly Lerner, Matthew Crocker, Kendra Todd, Brindha Rajagopalan, Clarisha Ware, Mark Bridge, Johnson Vo, Hannah Dragomanovich, Julie Sudduth-Klinger, Gina Vaccaro, Charles D Lopez, Margaret Tempero, Lisa M Coussens, Lawrence Fong
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC. Methods Previously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality. Results In the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator + (ICOS + ) CD4 + T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10 + B-cell frequency. Monotherapy also led to a trend in increased mature CD208 + dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1 – ) eomesodermin (EOMES + )) CD8 + T-cell frequency, with a concomitantly decreased dysfunctional (PD-1 + EOMES + ) CD8 + T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation. Conclusion Ibrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors. Trial registration number NCT02562898 .
Spontaneous, naturally occurring cancers in non-human primates as a translational model for cancer immunotherapy
Authors: Simon Deycmar, Bruno Gomes, Jehad Charo, Maurizio Ceppi, J Mark Cline
Journal: Journal for ImmunoTherapy of Cancer (2023)

The complexity of cancer immunotherapy (CIT) demands reliable preclinical models to successfully translate study findings to the clinics. Non-human primates (NHPs; here referring to rhesus and cynomolgus macaques) share broad similarities with humans including physiology, genetic homology, and importantly also immune cell populations, immune regulatory mechanisms, and protein targets for CIT. Furthermore, NHP naturally develop cancers such as colorectal and breast cancer with an incidence, pathology, and age pattern comparable to humans. Thus, these tumor-bearing monkeys (TBMs) have the potential to bridge the experimental gap between early preclinical cancer models and patients with human cancer.This review presents our current knowledge of NHP immunology, the incidence and features of naturally-occurring cancers in NHP, and recent TBM trials investigating CIT to provide a scientific rationale for this unique model for human cancer.